Opposing effects of HLA class I molecules in tuning autoreactive CD8+ T cells in multiple sclerosis.
The major known genetic risk factors in multiple sclerosis reside in the major histocompatibility complex (MHC) region. Although there is strong evidence implicating MHC class II alleles and CD4(+) T cells in multiple sclerosis pathogenesis, possible contributions from MHC class I genes and CD8(+) T cells are controversial. We have generated humanized mice expressing the multiple sclerosis-associated MHC class I alleles HLA-A(*)0301 (encoding human leukocyte antigen-A3 (HLA-A3)) and HLA-A(*)0201 (encoding HLA-A2) and a myelin-specific autoreactive T cell receptor (TCR) derived from a CD8(+) T cell clone from an individual with multiple sclerosis to study mechanisms of disease susceptibility. We demonstrate roles for HLA-A3-restricted CD8(+) T cells in induction of multiple sclerosis-like disease and for CD4(+) T cells in its progression, and we also define a possible mechanism for HLA-A(*)0201-mediated protection. To our knowledge, these data provide the first direct evidence incriminating MHC class I genes and CD8(+) T cells in the pathogenesis of human multiple sclerosis and reveal a network of MHC interactions that shape the risk of multiple sclerosis.
Friese
Manuel A
MA
Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Headley Way, Oxford, UK.
Jakobsen
Karen B
KB
Friis
Lone
L
Etzensperger
Ruth
R
Craner
Matthew J
MJ
McMahon
Róisín M
RM
Jensen
Lise T
LT
Huygelen
Véronique
V
Jones
E Yvonne
EY
Bell
John I
JI
Fugger
Lars
L
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002490:Central Nervous System / Q000276:immunology; D005786:Gene Expression Regulation; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000276:immunology
D015395:Histocompatibility Antigens Class I; D011948:Receptors, Antigen, T-Cell